2-240029975-C-T

Variant names:

• chr2-240029975-C-T
• rs758263312
• NM_001005853.1:c.455G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001005853.1(OR6B2):​c.455G>A​(p.Gly152Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000816 in 1,225,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G152A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: OR6B2 NM_001005853.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.06
• Publications: 0 publications found

Genes affected

OR6B2 (HGNC:15041): (olfactory receptor family 6 subfamily B member 2) Olfactory receptors interact with odorant molecules in the nose, to initiate a neuronal response that triggers the perception of a smell. The olfactory receptor proteins are members of a large family of G-protein-coupled receptors (GPCR) arising from single coding-exon genes. Olfactory receptors share a 7-transmembrane domain structure with many neurotransmitter and hormone receptors and are responsible for the recognition and G protein-mediated transduction of odorant signals. The olfactory receptor gene family is the largest in the genome. The nomenclature assigned to the olfactory receptor genes and proteins for this organism is independent of other organisms. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR6B2	NM_001005853.1	c.455G>A	p.Gly152Asp	missense_variant	Exon 1 of 1	ENST00000319423.5	NP_001005853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OR6B2	ENST00000319423.5	c.455G>A	p.Gly152Asp	missense_variant	Exon 1 of 1	6	NM_001005853.1	ENSP00000322435.5

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 8.16e-7 AC: 1 AN: 1225818 Hom.: 0 Cov.: 18 AF XY: 0.00000162 AC XY: 1 AN XY: 617962

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 28460

American (AMR) AF: 0.00 AC: 0 AN: 40924

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24366

East Asian (EAS) AF: 0.00 AC: 0 AN: 37796

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 79966

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5274

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 904240

Other (OTH) AF: 0.00 AC: 0 AN: 52500

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.046	T
Eigen	Uncertain	0.21
Eigen_PC	Benign	-0.049
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0080	T
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.43	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		1.1
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.71		Loss of glycosylation at S151 (P = 0.3424);
MVP		0.74
MPC		1.9
ClinPred		0.98	D
GERP RS		2.5
PromoterAI		0.028	Neutral
Varity_R		0.83
gMVP		0.77
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs758263312; hg19: chr2-240969392; COSMIC: COSV108051267; COSMIC: COSV108051267;